Biology subjects

Bengoetxea de Tena, I.

Publications and source records attributed to Bengoetxea de Tena, I..

4 recordsLinked to original sources

bioRxiv2024

Cannabinoid agonist WIN55,212-2 prevents scopolamine-induced impairment of spatial memory

The endocannabinoid system is involved in diverse processes, like learning and memory, governed by cholinergic neurotransmission. Recent research demonstrates that in a model of dementia derived from basal forebrain cholinergic degeneration, WIN55,212-2 improves cognition through increased cortical choline levels. However, the effect of cannabinoids on cholinergic deficits is still under investigation. In this work, we studied the effect of this treatment in a pharmacological model of transient cholinergic hypofunction by the acute administration of the muscarinic antagonist, scopolamine, in spatial, recognition and aversive memory tests. Scopolamine induced memory impairment was observed in the three tests and, importantly, the cannabinoid subchronic treatment with low doses of WIN55,212-2 prevented this deleterious effect in spatial memory when evaluated in spatial Barnes maze test. Autoradiographic studies indicate that, following the WIN55,212-2 treatment, cannabinoid receptor density increased in the motor and somatosensory cortices. In layers I-V of the motor cortex, the activity of cannabinoid and muscarinic receptors also increased. These results suggest that WIN55,212-2, through the activation of CB1 receptors, indirectly elevates the muscarinic tone in key cortical areas for learning and memory, preventing the memory deficits induced by scopolamine specifically in spatial memory. This highlights the importance of the crosstalk between the endocannabinoid and the cholinergic system for learning and memory processes and suggest that cannabinoid agonists might be an alternative for the treatment of cognitive deficits associated with cholinergic dysfunction.

pharmacology and toxicology↗

bioRxiv2024

Synthesis and pharmacological characterization of UVI3502, a novel cannabinoid receptor 1 (CB1) antagonist/inverse agonist

The endocannabinoid (eCB) system regulates several brain functions and is implicated in neurological disorders. The pharmacological blockade of cannabinoid receptors has a therapeutic potential for various cognitive deficits, but also produces severe psychiatric side effects. Hence, new cannabinoid compounds that potentiate therapeutic effects, while minimizing toxicity, are required. In this study, we synthesized and characterized a novel antagonist/inverse agonist of CB1 receptors. UVI3502 showed affinity for two [3H]CP55,940 binding sites (IC50Hi 0.47 {+/-} 1.94 nM and IC50Lo 1470 {+/-} 1.80 nM). Subsequent binding assays performed in CB1 and CB2 overexpressing membranes determined that the low affinity binding site corresponded to CB1, but the high-affinity binding site of UVI3502 did not correspond to CB2 and the possibility of it corresponding to GPR55 was analyzed. The affinity of UVI3502 for CB1 receptors was further confirmed with neuroanatomical specificity by autoradiography in key brain areas, in which functional [35S]GTP{gamma}S assays demonstrated that UVI3502 behaved as an antagonist/inverse agonist of CB1 receptors, blocking the stimulation evoked by potent cannabinoid receptor agonist CP55,940 and decreasing basal [35S]GTP{gamma}S binding. The in silico characterization of the binding to CB1 receptor through molecular docking and molecular dynamics suggests that this activity is explained by the planar and rigid structure of UVI3502, which is optimal for interactions with the inactive state of the receptor. These results indicate that UVI3502 is a novel antagonist/inverse agonist of CB1 receptors, making it a compelling candidate for pharmacologically blocking cannabinoid receptors in the central nervous system. Significance StatementUVI3502 is a novel antagonist/inverse agonist of CB1 receptors, with almost no affinity for CB2 receptors and an additional high-affinity binding site for a third, cannabinoid-like receptor, potentially GPR55. In relevant brain areas for learning and memory processes with a high expression of CB1, UVI3502 blocks the stimulation evoked by the cannabinoid receptor agonist CP55,940, rendering it as an interesting compound for the pharmacological blockade of cannabinoid receptors in the central nervous system.

pharmacology and toxicology↗

bioRxiv2024

Cortical lipids containing choline mediate cannabinoid-induced cognitive improvement

Recent research connecting choline-containing lipids to basal forebrain cholinergic neurons (BFCN) degeneration in neuropathological states highlights a challenge for balancing lipid integrity with optimal acetylcholine (ACh) levels. Warranting an adequate choline source to maintain ACh levels in this pathway is crucial for preserving memory. The endocannabinoid (eCB) system plays a role in modulating learning and memory processes controlled by cholinergic neurotransmission. Consequently, we propose that activation of this system is neuroprotective against cholinergic degeneration. In the present study, we investigated the neuroprotective effect of a subchronic treatment with the CB1 cannabinoid agonist, WIN55,212-2, using both ex vivo and in vivo 192IgG-Saporin models of specific cholinergic damage. Degeneration of baso-cortical cholinergic pathways induced memory deficits and a downregulation of saturated and mono-unsaturated lysophosphatidylcholines (LPC) cortical levels. WIN55,212-2 not only restored memory deficits but also increased cortical ACh levels and modified cortical choline-containing lipids such as sphingomyelins (SM) and LPCs, which are essential for correct memory functioning, in lesioned animals. Given these results, we propose that WIN55,212-2 generates an alternative choline source through the breakdown of SMs, which is enough to increase cortical ACh levels and LPCs. These findings suggest that modification of choline-containing lipids by the activation of CB1 receptors is a promising therapy for dementia associated with cholinergic dysfunction, such as in Alzheimers disease (AD).

neuroscience↗

bioRxiv2024

Cell lipotypes localization in brain by mass spectrometry imaging

The study investigates brain lipid super-specialisation by defining characteristic spectral lipotypic profiles for the five primary cerebral cell-types. Utilizing a computational approach, the research visualizes the anatomical distribution of these profiles with high spatial resolution in brain tissues. This method unveils cellular stereotypic lipidic signatures within the CNS, providing a new framework for exploring the physiological roles of lipids in diverse cell-types present in brain or in any other tissue.

neuroscience↗